Exosome membrane-biomimetic nanomedicine targets the pre-metastatic niche via NF-κB inhibition to suppress breast cancer lung metastasis

Breast cancer lung metastasis remains a major cause of mortality, largely driven by the formation of a pre-metastatic niche (PMN) through inflammatory signaling. Here, we report a biomimetic nanomedicine, EXO@m(PDTC), designed to target the pulmonary PMN and inhibit metastasis via suppression of nuclear factor-κB (NF-κB) signaling. The nanoconstruct consists of pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, encapsulated within micelles coated with exosome membranes derived from breast cancer cells. This design leverages the innate lung-homing ability of tumor exosomes, enabling precise accumulation in incipient PMNs. We demonstrate that EXO@m(PDTC) effectively inhibits NF-κB activation in multiple pulmonary stromal cell types, downregulates pro-inflammatory cytokines, and attenuates PMN formation. In both tail vein and orthotopic breast cancer models, EXO@m(PDTC) significantly reduces lung metastasis with minimal systemic toxicity. Transcriptomic analysis further reveals downregulation of NF-κB-associated pathways, including cytokine-cytokine receptor interaction and chemokine signaling. Our study highlights a promising strategy for intercepting metastasis through early PMN disruption and offers a targeted nanotherapeutic platform with high clinical potential.